CN1544475A - Sulfated Polyguluronic Acid Ester and its preparation method and uses - Google Patents
Sulfated Polyguluronic Acid Ester and its preparation method and uses Download PDFInfo
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- CN1544475A CN1544475A CNA2003101057189A CN200310105718A CN1544475A CN 1544475 A CN1544475 A CN 1544475A CN A2003101057189 A CNA2003101057189 A CN A2003101057189A CN 200310105718 A CN200310105718 A CN 200310105718A CN 1544475 A CN1544475 A CN 1544475A
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- ancient sugar
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- sugar ester
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- 150000002148 esters Chemical class 0.000 title claims abstract description 50
- 239000002253 acid Substances 0.000 title claims abstract description 12
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 15
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000003814 drug Substances 0.000 claims abstract description 12
- 238000011282 treatment Methods 0.000 claims abstract description 12
- 230000015556 catabolic process Effects 0.000 claims abstract description 5
- 238000006731 degradation reaction Methods 0.000 claims abstract description 5
- 238000001035 drying Methods 0.000 claims abstract description 5
- 238000001914 filtration Methods 0.000 claims abstract description 4
- 238000000108 ultra-filtration Methods 0.000 claims abstract description 4
- 239000000126 substance Substances 0.000 claims abstract description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Chemical compound O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 claims description 8
- XTHPWXDJESJLNJ-UHFFFAOYSA-N sulfurochloridic acid Chemical group OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- -1 alkali metal salt Chemical class 0.000 claims description 6
- 238000001556 precipitation Methods 0.000 claims description 6
- AEMOLEFTQBMNLQ-BZINKQHNSA-N D-Guluronic Acid Chemical compound OC1O[C@H](C(O)=O)[C@H](O)[C@@H](O)[C@H]1O AEMOLEFTQBMNLQ-BZINKQHNSA-N 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- 235000006408 oxalic acid Nutrition 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 4
- 230000018044 dehydration Effects 0.000 claims description 3
- 238000006297 dehydration reaction Methods 0.000 claims description 3
- 238000010298 pulverizing process Methods 0.000 claims description 3
- PWEBUXCTKOWPCW-UHFFFAOYSA-N squaric acid Chemical compound OC1=C(O)C(=O)C1=O PWEBUXCTKOWPCW-UHFFFAOYSA-N 0.000 claims description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 2
- 235000015320 potassium carbonate Nutrition 0.000 claims description 2
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
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- 238000006467 substitution reaction Methods 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- 239000011593 sulfur Substances 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims 1
- 230000008021 deposition Effects 0.000 abstract description 4
- 229920000615 alginic acid Polymers 0.000 abstract description 2
- 235000010443 alginic acid Nutrition 0.000 abstract description 2
- 229960001126 alginic acid Drugs 0.000 abstract 1
- 239000000783 alginic acid Substances 0.000 abstract 1
- 150000004781 alginic acids Chemical class 0.000 abstract 1
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 238000009991 scouring Methods 0.000 abstract 1
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- 238000005670 sulfation reaction Methods 0.000 abstract 1
- 208000008281 urolithiasis Diseases 0.000 abstract 1
- 241000700159 Rattus Species 0.000 description 23
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 206010003694 Atrophy Diseases 0.000 description 2
- 229920002683 Glycosaminoglycan Polymers 0.000 description 2
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- RQALKBLYTUKBFV-UHFFFAOYSA-N 1,4-dioxa-7-thiaspiro[4.4]nonane Chemical compound O1CCOC11CSCC1 RQALKBLYTUKBFV-UHFFFAOYSA-N 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
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- 206010002091 Anaesthesia Diseases 0.000 description 1
- 241000632227 Antenoron Species 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 206010006987 Calculus bladder Diseases 0.000 description 1
- 206010053567 Coagulopathies Diseases 0.000 description 1
- 208000015924 Lithiasis Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 208000035992 Postmortem Changes Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 1
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A polyguluronic acid ester having a chemical name of L-polyguluronic aldonic acid-2, 3-sulfuric acid, is prepared through the steps of first obtaining L-polyguluronic aldonic acid through acid degradation and pH grading of alginic acid, proceeding secondary acid degradation and pH grading, carrying out ultrafiltration, deposition, dewatering and drying, using sulfating agent to subject the polyguluronic acid ester to sulfation, alcohol deposition, scouring, alkaline treatment, filtering, drying and disintegrating. The polyguluronic acid ester according to the invention has strong negative ion concentration property, it can be utilized in the preparation of medicament for treating or preventing urinary lithiasis.
Description
Technical field
The present invention relates to a kind of polysaccharide, relate in particular to a kind of sulfated polysaccharide ancient sugar ester and preparation method thereof and the application in anti-lithangiuria.
Background technology
Lithangiuria is the infringement people's health and reduces one of frequently-occurring disease of quality of life that sickness rate worldwide is higher, can go to a doctor once because of calculosis throughout one's life as 10% people is arranged approximately in western countries.China is one of calculous district occurred frequently, and more southern areas of China especially account for the first place of Urology Surgery number of hospitalized.Calculous another characteristics are that recurrence rate is very high, foreign study show the patient in the back 8 years recurrence rate of treatment greater than 50%.China studies show that the patient is about 70% in the back 9 years recurrence rate of treatment, and secular recurrence rate is up to more than 80%.In addition, the sickness rate of lithangiuria has the trend that rises year by year, and the sickness rate of seven, 80 years Chinese and westerns has in the past risen 70～100%.At present, the treatment of lithangiuria mainly is based on operative therapy, be aided with extracorporeal shock-wave lithotomy technology and PCN and get the stone technology, but because extracorporeal shock-wave lithotomy can cause the kidney endothelial injury, and residual microlith can become the parent nucleus of recurrence of hepatolithiasis again in the urinary tract of operation back, and therefore treatment back recurrence rate is very high.If now be used to prevent and treat some Chinese medicine classes of drug main of lithangiuria clinically, the Chinese patent medicine that is mostly based on Longhairy Antenoron Herb commonly used, mainly be to wriggle by diuretic properties and promotion unstriated muscle to discharge short grained calculus, but the calculus big to diameter is invalid, and can not block calculus formation and recurrence approach.The Potassium dihydrogen citrate mixture is most widely used small-molecule drug, thereby it mainly is by complexing calcium ions, reduces the urine calcium concn, improves the dissolving that the urine pH value promotes uric acid; Magnesium preparation can increase the solubleness of caoxalate, reduces the degree of supersaturation of urine.In addition, the uralyt of Germany's production also has better action to the treatment and the prevention of calculus.But above-mentioned these medicines also can not satisfy growing clinical needs far away.
Summary of the invention
The purpose of this invention is to provide a kind of ancient sugar ester, treat and prevent pressing for of lithangiuria clinically to satisfy.
A kind of ancient sugar ester is characterized in that chemical name is the poly-guluronic acid-2 of L-, the 3-sulfuric acid, and molecular formula is (C
6H
5O
6R
2M)
n, structural formula is as follows:
N=10-30 wherein, R=H or-SO
3M, M are an alkali metal salt.
A kind of preparation method of ancient sugar ester, it is characterized in that the poly-guluronic acid of L-that Lalgine is obtained through acid degradation and pH classification, carry out quadratic acid degraded and pH classification, again through ultrafiltration, precipitation, dehydration and drying, adopt then sulfur acidizing reagent to its carry out sulphating, again through alcohol precipitation, washing, with alkaline purification, filtration, oven dry and pulverizing.
Ancient sugar ester is used to prepare the medicine of prevention and treatment lithangiuria.
Ancient sugar ester is as a kind of sulfated polysaccharide compounds with strong polyanion character, its electric density is significantly higher than endogenic glycosaminoglycan, and the glycosaminoglycan in the urine is a kind of polyanionic macromolecule ionogen, have the crystal of inhibition and generate, grow, assemble, prevent multi-functionals such as crystal and cell interaction.Since the structure of ancient sugar ester and the singularity of charge distribution, and derive from the natural polysaccharide compounds, be expected to become a kind of novel prevention and the medicine of treatment lithangiuria, will have better market prospect.
Embodiment
The alginates water is mixed with the even glue of 1-3%, in 70-100 ℃ of water-bath with the salt acid degradation of 0.1-1.0M 6-10 hour, centrifugal abandoning supernatant, getting precipitation dissolves with dilute sodium hydroxide, under agitation condition, under the pH=2.85 condition, carry out classification, the flocks that generates is carried out quadratic acid degraded and pH classification by above-mentioned condition again after centrifugation with acid.Transfer pH to dissolving after with water-dispersion the precipitation that obtains, carry out ultrafiltration then and remove small molecules, again with 95% ethanol sedimentation of 3-4 times of volume, through dehydration be drying to obtain the higher poly-guluronic acid of purity.In ice-water bath, under agitation condition, the poly-guluronic acid of 10.0g slowly is added in the 100-150g sulphating reagent, finish and temperature of reaction is risen to 60-70 ℃, insulation reaction 1.5-3.5 hour.Reaction finishes back 95% ethanol sedimentation, the paste that can gather the guluronic acid sulfuric ester with 70% ethanol repetitive scrubbing, this paste water is formulated as 10% the aqueous solution, transform under the vacuum stirring condition with sodium hydroxide, use ethanol sedimentation again, and promptly get ancient sugar ester of the present invention through filtration, oven drying at low temperature and pulverizing.
Hydrochloric acid described in the present embodiment also can be used sulfuric acid, nitric acid or oxalic acid instead; Described sodium hydroxide also can be used yellow soda ash, sodium bicarbonate, potassium hydroxide, salt of wormwood or saleratus instead; Described sulphating reagent can be chlorsulfonic acid/methane amide, chlorsulfonic acid/dimethyl formamide, chlorsulfonic acid/pyridine, chlorsulfonic acid/sulfuric acid, sulphur trioxide/pyridine or sulphur trioxide/Trimethylamine 99.
Ancient sugar ester of the present invention is white or the amorphous powder of off-white color, slightly light saline taste, soluble in water, be insoluble to organic solvents such as ethanol, acetone, EC, the substitution value of sulfate group is 0.5-2.0, weight-average molecular weight is 5000-20000, molecular weight distribution width D＜1.8, and limiting viscosity is 5.0-14.0.Be the pharmacodynamics and the toxicological evaluation result of ancient sugar ester of the present invention below
(1) results of pharmacodynamic test of ancient sugar ester
1 ancient sugar ester causes the prophylactic effect of kidney of rats calculus to feeding ethylene glycol: select for use healthy male
Wistar kind rat (four experimentation on animals centers of institute of section of army provide), body weight 255 ~ 290g,
Random packet, 12 every group.Except that the normal control group, all contain 2% second two by the body weight feeding
The basal feed of alcohol+1% ammonium chloride carries out moulding, and in moulding, the administration group is irritated stomach and given
Give 25,50, the ancient sugar ester of 100mg/kg; Positive controls is irritated stomach and is given 50mg/kg's
Uralyt; Model control group is irritated stomach and is given distilled water, irritates the long-pending 0.5ml/100g that is of body of stomach
Body weight, once a day, continuous six weeks.After the off-test, put to death rat, get right kidney flushing
Clean and blot, add 10ml 0.1mol/LHCL after weighing and be ground into homogenate, left standstill 48 hours
After, centrifugal, get supernatant liquor, measure kidney oxalic acid and kidney respectively with colorimetry and complexometry
The content of calcium carries out statistical study with t-value method.Test-results shows: the ancient sugar ester prevention
Six weeks of administration, 50,100mg/Kg dosage group obviously reduces ethylene glycol and cause the kidney of rats calculus
Kidney oxalic acid, kidney calcium contents; The kidney pathological examination shows, 25,50,100mg/Kg dosage
Group all improves significantly to deposition, the renal lesions of kidney stone, shows second two
The formation that alcohol causes the kidney of rats calculus has tangible prophylactic effect.
2 ancient sugar esters cause the therapeutic action of kidney of rats calculus to feeding ethylene glycol: select for use healthy male
Wistar kind rat carries out moulding one month by method in above-mentioned 1, uses common raising then instead
Material also carries out drug treatment simultaneously.Test-results shows: ancient sugar ester treatment administration one month,
50, the 100mg/Kg dosage group kidney oxalic acid, the kidney calcium that obviously reduce moulding kidney of rats calculus contains
Amount; The kidney pathological examination shows that 100mg/Kg dosage group is to deposition, the kidney of kidney stone
The popular name for change all improves significantly, and shows that large mouse with renal calculs is had obvious treatment to be done
With.
3 ancient sugar esters are to the cystolithic prophylactic effect of the property implanted: select for use healthy male Wistar kind big
Mouse under aseptic condition, is cut bladder approximately with vetanarcol anesthesia backs (40mg/kg)
3mm implants one of circular zinc granule and (weighs 38.1 ~ 43.4mg), close bladder and stomach wall, seam
Close skin.And after operation, gave intramuscular injection penicillin 25mg/kg in 6,12,24,48 hours,
Prohibited water simultaneously 12 hours, the administration of dividing into groups then.The administration group irritates that stomach gives 25,50,100mg/kg
Ancient sugar ester; Positive controls is irritated the uralyt that stomach gives 100mg/kg; Model control group
Irritate stomach and give distilled water, the filling body of stomach is long-pending to be the 0.5ml/100g body weight, once a day, connects
Continuous six weeks.Experiment is opened bladder after finishing, and takes out calculus and weighs, and unites with t-value method
Score is analysed.Test-results shows: the rat that ancient sugar ester is implanted zinc granule to bladder, continuous irrigation stomach
Six weeks of administration, 50, obviously to suppress with zinc be the vesical calculus of core to 100mg/Kg dosage group
Formation, show that ancient sugar ester has tangible prophylactic effect to cystolithic formation.
4 ancient sugar esters are to the cystolithic therapeutic action of the property implanted: select for use healthy male Wistar kind big
Mouse is implanted with zinc by method in above-mentioned 3 and is one in the rat bladder calculus of core, and is above-mentioned then
Method is observed ancient sugar ester to the cystolithic therapeutic action of the property implanted in 3.The test-results table
Bright: it is the cystolithic rat of core that ancient sugar ester is implanted with zinc to bladder, and the continuous irrigation stomach is given
Six weeks of medicine, 50,100mg/Kg dosage group obviously suppresses cystolithic growth, shows Gu
Sugar ester has tangible litholytic effect.
(2) general pharmacology of ancient sugar ester is learned test-results
1 mouse once irritate stomach give ancient sugar ester by 200,400,800,2000mg/Kg dosage, with
Control group compares, and the mouse behavioral activity does not have considerable change, shows that ancient sugar ester is to the mouse nervous system
System does not have obviously influence.
2 anesthetized dogs once irritate stomach give ancient sugar ester by 25,50,100mg/Kg dosage, observe continuously
4 hours, each administration group and control group compared, and amplitude of respiration, frequency, mean arterial pressure reach
Electrocardiogram(ECG does not have considerable change, shows respiratory system, the cardiovascular systems of ancient sugar ester to anesthetized dog
There is not obviously influence.
(3) The acute toxicity tests of ancient sugar ester
The LD of 1 rat intravenous injection ancient sugar ester
50And the 95% credible 2.25g/kg that is limited to, mouse vein is annotated
Penetrate the LD of ancient sugar ester
50And the LD of 95% fiducial limit
50Be 6.29g/kg.
2 ancient sugar esters once irritate after stomach gives 10g/kg, 25g/kg for large and small mouse respectively, animal
Outward appearance, behavioral activity Non Apparent Abnormality, mouth, nose, the no abnormal secretory product of eye.
(4) the long term toxicity test result of ancient sugar ester
1 ancient sugar ester with 200,600,2000mg/Kg dosage give the continuous gastric infusion of rat 6 months and
Drug withdrawal recovered 1 month, carried out overview, hematology, blood biochemical, pathological tissue
Learn and check.Test-results shows, high dose group male rat (4-26 week), female rats
(5-12 week) body weight gain is starkly lower than control group; 3 months high dose group of administration are female
Rat total protein (TP) is lower than control group (P＜0.05); 6 months high dose group of administration are female
Property rat, male rat liver, kidney organ coefficient all obviously greater than control group (P＜0.05,
P＜0.05), female rats total protein (TP), albumin (ALP) are all obviously greater than contrast
Group (P＜0.05, P＜0.05).Administration phase, decubation all the other each administration group rats each
Item detects index and the relatively more equal no significant difference of control group.Histopathologic examination does not also find
The pathological change relevant with medicine.Therefore, ancient sugar ester is anti-to the nontoxicity of rat oral gavage administration
Answering dosage is 600mg/Kg.
2 than lattice dog continuous oral ancient sugar ester 180 days, and 1000mg/Kg dosage treated animal is during administration
Slight gastrointestinal reaction (appetite descend, just rare) be interrupted to appear, to the spirit of animal,
Activity, anus temperature, body weight, urine do not exert an influence; Electrocardioscopy, eye examination,
Examination of bone marrow smear and control group are not seen considerable change; Blood red egg is found in hematological examination
In vain, red corpuscle, pcv obviously raise and the clotting time obviously prolongs; Pathological tissue
Learn and check the obvious atrophy of discovery thymus gland, renal cells is slight, and cloudy swelling sex change and small intestine are sticking
The slight extravasated blood of film, the obvious active proliferation of reticuloendothelial system.Checked in 30 days after the drug withdrawal, on
The pathological change of stating all internal organs obviously alleviates.300mg/Kg dosage treated animal is in the administration phase
Between individual animal slight gastrointestinal reaction appears, hematological examination find thrombocyte increase,
Cruor time extending; Histopathologic examination finds the obvious atrophy of thymus gland, and renal tubular epithelial is thin
Born of the same parents the are slight slight extravasated blood of cloudy swelling sex change and mucous membrane of small intestine, the obvious hyperplasia work of reticuloendothelial system
Jump.The pathological change of checking above-mentioned all internal organs after the drug withdrawal in 30 days obviously alleviates.100mg/Kg
The dosage treated animal is not also found to be drawn by medicine through blood biochemical analysis and histopathologic examination
The overt toxicity reaction that rises, this dosage is not for observing the dosage of toxic reaction.
(5) the special toxicity test result of ancient sugar ester
Irritate stomach in rat sensitive period of teratogenesis (pregnant 6-15 day) oral administration and give ancient sugar ester 30,120 and 480mg/Kg, and establish control group, dissected in 20th in rat gestation.The result shows: ancient sugar ester dosage did not cause tangible embryotoxicity and teratogenesis tire effect at 30-480mg/Kg days.
Claims (7)
1 one kinds of ancient sugar esters is characterized in that chemical name is the poly-guluronic acid-2 of L-, the 3-sulfuric acid, and molecular formula is (C
6H
5O
6R
2M)
n, structural formula is as follows:
N=10-30 wherein, R=H or-SO
3M, M are an alkali metal salt.
2 ancient sugar esters as claimed in claim 1, the sulfate group substitution value that it is characterized in that described sulfuric acid is 0.5-2.0, weight-average molecular weight is 5000-20000.
The preparation method of 3 one kinds of ancient sugar esters, it is characterized in that the poly-guluronic acid of L-that Lalgine is obtained through acid degradation and pH classification, carry out quadratic acid degraded and pH classification, again through ultrafiltration, precipitation, dehydration and drying, adopt then sulfur acidizing reagent to its carry out sulphating, again through alcohol precipitation, washing, with alkaline purification, filtration, oven dry and pulverizing.
4 preparation methods as claimed in claim 3 is characterized in that described acid is hydrochloric acid, sulfuric acid, nitric acid or oxalic acid.
5 preparation methods as claimed in claim 3 is characterized in that described alkali is sodium hydroxide, yellow soda ash, sodium bicarbonate, potassium hydroxide, salt of wormwood or saleratus.
6 preparation methods as claimed in claim 3 is characterized in that described sulphating reagent is chlorsulfonic acid/methane amide, chlorsulfonic acid/dimethyl formamide, chlorsulfonic acid/pyridine, chlorsulfonic acid/sulfuric acid, sulphur trioxide/pyridine or sulphur trioxide/Trimethylamine 99.
7 ancient sugar esters are used to prepare the medicine of prevention and treatment lithangiuria.
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